NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile) AND Long QT syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 13, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000781487.12

Allele description [Variation Report for NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile)]

NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile)

Gene:

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile)

HGVS:

NC_000007.14:g.150951505C>T
NG_008916.1:g.31422G>A
NM_000238.4:c.1888G>AMANE SELECT
NM_001204798.2:c.868G>A
NM_001406753.1:c.1600G>A
NM_001406755.1:c.1711G>A
NM_001406756.1:c.1600G>A
NM_001406757.1:c.1588G>A
NM_172056.3:c.1888G>A
NM_172057.3:c.868G>A
NP_000229.1:p.Val630Ile
NP_000229.1:p.Val630Ile
NP_001191727.1:p.Val290Ile
NP_001393682.1:p.Val534Ile
NP_001393684.1:p.Val571Ile
NP_001393685.1:p.Val534Ile
NP_001393686.1:p.Val530Ile
NP_742053.1:p.Val630Ile
NP_742053.1:p.Val630Ile
NP_742054.1:p.Val290Ile
NP_742054.1:p.Val290Ile
LRG_288t1:c.1888G>A
LRG_288t2:c.1888G>A
LRG_288t3:c.868G>A
LRG_288:g.31422G>A
LRG_288p1:p.Val630Ile
LRG_288p2:p.Val630Ile
LRG_288p3:p.Val290Ile
NC_000007.13:g.150648593C>T
NM_000238.3:c.1888G>A
NM_172056.2:c.1888G>A
NM_172057.2:c.868G>A
NR_176254.1:n.2296G>A
NR_176255.1:n.1169G>A

Protein change:

V290I

Links:

dbSNP: rs199472958

NCBI 1000 Genomes Browser:

rs199472958

Molecular consequence:

NM_000238.4:c.1888G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.868G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1600G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1711G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1600G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1588G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1888G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.868G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919554	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 25, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30041777, 28449774 Citation Link,
SCV001400343	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9693036, 16432067, 23303164, 8799887, 28449774, 28492532
SCV004814298	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8799887, 28449774, 30041777, 32893267, 34363016, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919554

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Oct 25, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001400343

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004814298

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.

Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT.

Genomics. 1998 Jul 1;51(1):86-97.

PubMed [citation]

PMID:: 9693036

Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism.

Anderson CL, Delisle BP, Anson BD, Kilby JA, Will ML, Tester DJ, Gong Q, Zhou Z, Ackerman MJ, January CT.

Circulation. 2006 Jan 24;113(3):365-73.

PubMed [citation]

PMID:: 16432067

See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919554.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: KCNH2 c.1888G>A (p.Val630Ile) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 277200 control chromosomes (gnomAD). The variant, c.1888G>A, has been reported in the literature in individuals affected with sudden arrhythmic death syndrome and long QT syndrome (Lahrouchi_2017, Owen_2018). These data indicate that the variant may be associated with disease. In addition, other missense changes affecting the same codon, p.V630A and p.V630L, and nearby p.N629S, p.N629K, p.N629I, p.N629D, and p.S631A, have been reported in affected individuals suggesting this region could be important for KCNH2 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely pathogenic. Therefore, based on the variant fulfilling the following ACMG criterias: PM1,PM5,PP3, and PP5, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001400343.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Val630 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9693036, 16432067, 23303164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 8799887). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 222669). This missense change has been observed in individual(s) with sudden cardiac death (PMID: 28449774). This variant is present in population databases (rs199472958, gnomAD 0.005%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 630 of the KCNH2 protein (p.Val630Ile).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004814298.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces valine with isoleucine at codon 630 of the KCNH2 protein. This variant is found within a highly conserved pore region (a.a.612-632). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant has no significant impact on channel function (PMID: 8799887). This variant has been reported in five unrelated individuals affected with or suspected of having long QT syndrome (PMID: 30041777, 32893267, communication with external laboratories ClinVar SCV000263978.2, SCV002723839.1), and in an individual affected with Brugada syndrome (PMID: 34363016), ventricular arrhythmias (ClinVar SCV001754799.1), or sudden arrhythmic death syndrome (PMID: 28449774). This variant has also been observed in individuals with other conditions, including epilepsy, dilated cardiomyopathy and muscular dystrophy, and multiple congenital abnormalities (communication with external laboratories ClinVar SCV002723839.1, SCV001400343.4). This variant has been identified in 7/282860 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Val630Ala, has been determined to be pathogenic (ClinVar variation ID: 67319, Color), indicating that valine at this position is important for KCNH2 protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: May 1, 2024

ClinVar

Relating variation to medicine